Triazole Analogues Research Articles

Synthesis, crystal structure, and reactive oxygen species (ROS) inhibition of N– and O–linked triazole analogues of harmine

Reactive oxygen species (ROS) have been reported in the literature for their important role in the progression of oxidative stress which results in several pathological conditions, including Alzheimer's and Parkinson's disease, cancer, arthritis, diabetes, atherosclerosis, and autoimmune disease. Anti-inflammatory agents are important to control over production of ROS. However, several side effects are associated with the reported marketed drugs. In present study, two new series of harmine linked–triazoles (5–25) were designed as potential anti-inflammatory agents, based on the reported anti-inflammatory effect of harmine alkaloid. Triazole compounds were prepared via copper-catalyzed 1,3-dipolar cycloaddition reaction between azidoacetophenones and N-propargyl harmine under green conditions with high yields and short reaction times. Compounds 2, 3, 6–8, 10, 12, 14, 17, 19, 20, and 22 showed a potent ROS inhibitory activity with IC50 values between 1.1 ± 0.1 to 7.5 ± 0.7 µg/mL, compared to the standard, ibuprofen (IC50 = 11.2 ± 1.9 µg/mL). Also, compounds are found to be non-cytotoxic against NIH 3T3 cell line, except a small set of compounds, including 9, 12, 21, and 25. The synthesized harmine-linked triazoles may emerge as attractive building blocks in the search of new anti-inflammatory agents.

Copper-Catalyzed Azide-Alkyne Cycloaddition of Hydrazoic Acid Formed In Situ from Sodium Azide Affords 4-Monosubstituted-1,2,3-Triazoles.

We report a copper-catalyzed cycloaddition of hydrogen azide (hydrazoic acid, HN3) with terminal alkynes to form 4-substituted-1H-1,2,3-triazoles in a sustainable manner. Hydrazoic acid was formed in situ from sodium azide under acidic conditions to react with terminal alkynes in a copper-catalyzed reaction. Using polydentate N-donor chelating ligands and mild organic acids, the reactions were realized to proceed at room temperature under aerobic conditions in a methanol–water mixture and with 5 mol % catalyst loadings to afford 4-substituted-1,2,3-triazoles in high yields. This method is amenable on a wide range of alkyne substrates, including unprotected peptides, showing diverse functional group tolerance. It is applicable for late-stage functionalization synthetic strategies, as demonstrated in the synthesis of the triazole analogue of losartan. The preparation of orthogonally protected azahistidine from Fmoc-l-propargylglycine was realized on a gram scale. The hazardous nature of hydrazoic acid has been diminished as it forms in situ in <6% concentrations at which it is safe to handle. Reactions of distilled solutions of hydrazoic acid indicated its role as a reactive species in the copper-catalyzed reaction.

Pyrazole and Triazole Derivatives as Mycobacterium tuberculosis UDP-Galactopyranose Inhibitors.

UDP-galactopyranose mutase (UGM) is an essential enzyme involved in the bacterial cell wall synthesis, and is not present in mammalian cells. Thus, UGM from Mycobacterium tuberculosis (Mtb) represents a novel and attractive drug target for developing antituberculosis agents. A pyrazole-based compound, MS208, was previously identified as a mixed inhibitor of MtbUGM which targets an allosteric site. To understand more about the structure activity relationship around the MS208 scaffold as a MtbUGM inhibitor, thirteen pyrazoles and triazole analogues were synthesized and tested against both MtbUGM and Mycobacterium tuberculosis in vitro. While the introduced structural modifications to MS208 did not improve the antituberculosis activity, most of the compounds showed MtbUGM inhibitory activity. Interestingly, the pyrazole derivative DA10 showed a competitive model for MtbUGM inhibition with improved Ki value of 51 ± 4 µM. However, the same compound did not inhibit the growth of Mycobacterium tuberculosis.

Thiamine analogues as inhibitors of pyruvate dehydrogenase and discovery of a thiamine analogue with non-thiamine related antiplasmodial activity.

A series of derivatives of a triazole analogue of thiamine has been synthesised. When tested as inhibitors of porcine pyruvate dehydrogenase, the benzoyl ester derivatives proved to be potent thiamine pyrophosphate (TPP) competitive inhibitors, with the affinity of the most potent analogue (Ki = 54 nM) almost matching the affinity of TPP itself. When tested as antiplasmodials, most of the derivatives showed modest activity (IC50 value >60 μM), except for a 4′-N-benzyl derivative, which has an IC50 value in the low micromolar range. This activity was not affected by increasing the extracellular concentration of thiamine in the culture medium for any of the compounds (except a modest increase in the IC50 for the unfunctionalized benzoyl ester), nor by overexpressing thiamine pyrophosphokinase in the parasite, making it unlikely to be due to an effect on thiamine transport or metabolism.

New bis- and tetrakis-1,2,3-triazole derivatives: Synthesis, DNA cleavage, molecular docking, antimicrobial, antioxidant activity and acid dissociation constants

In this study, a series of bis– and tetrakis–1,2,3–triazole derivatives were synthesized using copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry in 73–95% yield. The bis– and tetrakis–1,2,3–triazoles exhibited significant DNA cleavage activity while the tetrakis–1,2,3–triazole analog 6g completely degraded the plasmid DNA. Molecular docking simulations suggest that compound 6g acts as minor groove binder of DNA by binding through several noncovalent interactions with base pairs. All bis- and tetrakis–1,2,3-triazole derivatives were screened for antibacterial activity against E. coli, B. cereus, S. aureus, P. aeruginosa, E. hirae, L. pneumophila subsp. pneumophila strains and antifungal activity against microfungus C. albicans and C. tropicalis strains. Compound 4d exhibited the best antibacterial activity among bis–1,2,3–triazoles against E. coli and E. hirae, while 6c exhibited the best antibacterial activity among tetrakis–1,2,3–triazoles against E. hirae. Furthermore, the best antifungal activity against C. albicans and C. tropicalis was reported for the compound 5, while 6d displayed the best antifungal activity against C. tropicalis and C. albicans. Reasonable iron chelating activities and DPPH radical scavenging abilities were found for some of the compounds. Finally, the acid dissociation constants (pKa) of the bis–1,2,3–triazoles were also determined with the help of HYPERQUAD program using the data obtained from potentiometric titrations. The reported data here concludes that the bis- and tetrakis-1,2,3-triazoles are important cores that should be considered for further development of especially new anticancer agents acting through the DNA cleavage activity.

Design, synthesis and anti-TNBC activity of Azeliragon triazole analogues

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Many studies have shown a significant increase in the marker signal of the receptor for advanced glycation end-products (RAGE) with the malignant progression of tumor growth, metastasis and recurrence of breast cancer, including TNBC of primary tumors and lymph node metastases. Azeliragon is a RAGE inhibitor and it has been shown to actively inhibit the TNBC cell line, SUM149 (IC50 = 5.292 ± 0.310 μM). In order to develop a new anti-TNBC agent, we designed, synthesized and screened 26 Azeliragon triazole analogues to determine their anti-TNBC activities in vitro. The most active compound was KC-10 with an IC50 value of 0.220 ± 0.034 μM.

Efficient Dimerization Disruption of Leishmania infantum Trypanothione Reductase by Triazole-phenyl-thiazoles.

Inhibition of Leishmania infantum trypanothione disulfide reductase (LiTryR) by disruption of its homodimeric interface has proved to be an alternative and unexploited strategy in the search for novel antileishmanial agents. Proof of concept was first obtained by peptides and peptidomimetics. Building on previously reported dimerization disruptors containing an imidazole-phenyl-thiazole scaffold, we now report a new 1,2,3-triazole-based chemotype that yields noncompetitive, slow-binding inhibitors of LiTryR. Several compounds bearing (poly)aromatic substituents dramatically improve the ability to disrupt LiTryR dimerization relative to reference imidazoles. Molecular modeling studies identified an almost unexplored hydrophobic region at the interfacial domain as the putative binding site for these compounds. A subsequent structure-based design led to a symmetrical triazole analogue that displayed even more potent inhibitory activity over LiTryR and enhanced leishmanicidal activity. Remarkably, several of these novel triazole-bearing compounds were able to kill both extracellular and intracellular parasites in cell cultures.

Computational Inhibition Studies of the Human Proteasome by Apigenin-7-methyl ether and its Triazole Analogues with Subunit Specificity to the β1, β2 and β5 Catalytic Sites

Flavonoids are a multi-functional compound that possess characteristics that can be developed for therapeutic agents targeting several chronic diseases. In this computational study we have studied the binding of one flavonoid, apigenin and its triazole derivatives to the human proteasome β1, β2 and β5 catalytic sites. The computational procedure followed could be used as a platform for designing new subunit-specific inhibitors of the proteasome. The triazole analogues of apigenin have shown better binding than apigenin using the molecular docking technique. Τhe average binding energies obtained from 3 docking simulations suggest that apigenin has a binding energy of 8.89 kcal/mol, 7.79 kcal/mol and 7.59 kcal/mol for the β1, β2 and β5 catalytic sites, respectively. We found that a synthetically accessible analogue of apigenin, analogue 3c has an improved binding energy of -9.98 kcal/mol and of -10.28 kcal/mol to β1 and β5, respectively. Notable is that apigenin analogue 3a had an improved binding energy of -10.59 kcal/mol for β2 and the highest specificity for this catalytic site compared to the remaining sites. This shows that the substituted triazole moieties have significantly improved binding energies and specificities for the proteasome catalytic sites, which explains their recently found anti-cancer properties [1].

Treatment with a triazole inhibitor of the mitochondrial permeability transition pore fully corrects the pathology of sapje zebrafish lacking dystrophin

High-throughput screening identified isoxazoles as potent but metabolically unstable inhibitors of the mitochondrial permeability transition pore (PTP). Here we have studied the effects of a metabolically stable triazole analog, TR001, which maintains the PTP inhibitory properties with an in vitro potency in the nanomolar range. We show that TR001 leads to recovery of muscle structure and function of sapje zebrafish, a severe model of Duchenne muscular dystrophy (DMD). PTP inhibition fully restores the otherwise defective respiration in vivo, allowing normal development of sapje individuals in spite of lack of dystrophin. About 80 % sapje zebrafish treated with TR001 are alive and normal at 18 days post fertilization (dpf), a point in time when not a single untreated sapje individual survives. Time to 50 % death of treated zebrafish increases from 5 to 28 dpf, a sizeable number of individuals becoming young adults in spite of the persistent lack of dystrophin expression. TR001 improves respiration of myoblasts and myotubes from DMD patients, suggesting that PTP-dependent dysfunction also occurs in the human disease and that mitochondrial therapy of DMD with PTP-inhibiting triazoles is a viable treatment option.

Unravelling the potency of triazole analogues for inhibiting α-synuclein fibrillogenesis and in vitro disaggregation.

A series of triazole-based compounds was synthesized using a click chemistry approach and evaluated for the inhibition of α-synuclein (α-syn) fibrillogenesis and its disaggregation. Compounds Tr3, Tr7, Tr12, Tr15, and Tr16 exhibited good effect in inhibiting α-syn fibrillogenesis confirmed by Thioflavin-T assay and fluorescence microscopy and α-syn disaggregation confirmed by fluorescence microscopy. Molecular docking was used to understand the plausible mechanism of the test compounds for inhibiting the α-syn fibrillogenesis and to verify the in vitro results. Compounds Tr3, Tr7, Tr12, Tr15 and Tr16 showed good binding interactions with the essential amino acid residues of α-syn. The compounds which were found to be good inhibitors or disaggregators had no toxic effects on the SH-SY5Y cell line. These compounds have the potential to be developed as therapeutic interventions against synucleinopathies including Parkinson's disease and Lewy body dementia.

Computer-aided modeling of triazole analogues, docking studies of the compounds on DNA gyrase enzyme and design of new hypothetical compounds with efficient activities

The increasing problem of multi-drug resistant-tuberculosis has focused attention on developing new drugs that are not only active against drug-resistant tuberculosis, but also shorten the lengthy therapy. Therefore, this work employs the application of modeling technique to predict the inhibition activities of some prominent compounds which been reported to be efficient against Mycobacterium tuberculosis. To accomplish the purpose of this work, multiple regression and genetic function approximation were adopted to create the model. The established model was swayed with topological descriptors; MATS7s, SpMin4_Bhv, TDB3v and RDF70v. More also, interactions between the compounds and the target protein ‘DNA gyrase’ were evaluated via molecular docking approach utilizing the PyRx and discovery studio simulation software. Based on the docking analysis, compound 20 has the most noticeable binding affinity of −16.5 kcal/mol. Therefore, compound 20 served as a reference structural template and insight to design fourteen novel hypothetical agents with more prominent anti-tubercular activities. More also, compound 20j was observed with the highest activity among the designed compounds with a prominent binding affinity of −24.3 kcal/mol. Therefore, this research recommends in-vivo, in-vitro screening and pharmacokinetic properties to be carried out in order to determine the toxicity of the designed compounds. Communicated by Ramaswamy H. Sarma

Isomannide monoundecenoate‐based 1,2,3‐triazoles: Design, synthesis, and in vitro bioactive evaluation

AbstractA new series of isomannide monoundecenoate‐based 1,2,3‐triazole analogs 6a–e were designed by employing click chemistry in good yields. in vitro bioactive assay manifested that the several target compounds exhibited promising antibacterial and antifungal activities. Notably, compounds having phenyl substituted triazole 6a, and hydroxy phenyl substituted triazole 6b possessed highly selective promising inhibition towards Gram‐positive bacterial strains namely Bacillus subtilis and Staphylococcus aureus with MIC value of 3.9 μg/mL. Further, these potential hybrids (6a and 6b) also exhibited highly impressive antifungal activity against the tested panel of Candida strains with MIC value of 3.9 μg/mL. Based on our in vitro preliminary antimicrobial study, these two compounds 6a and 6b have been identified as potential antimicrobial lead compounds. Moreover, all prepared derivatives were also evaluated for their in vitro cytotoxic activities against A549, MCF7, DU145 and HeLa cancer cell lines. The results indicated that only the hydroxy phenyl substituted triazole analog 6b displayed good cytotoxic activity towards all tested human cancer cell lines without any significant effects on normal cell line (HUVEC).

Design, synthesis, and in vitro evaluation of novel triazole analogues featuring isoxazole moieties as antifungal agents

In order to develop novel antifungal agents, based on our previous work, a series of (2R,3R)-3-((3-substitutied-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (a1-a26) were designed and synthesized. All of the compounds exhibited good in vitro antifungal activities against eight human pathogenic fungi. Among them, compound a6 showed excellent inhibitory activity against Candida albicans and Candida parasilosis with MIC80 values of 0.0313 μg/mL. In addition, compounds a6, a9, a12, a13 and a14 exhibited moderate inhibitory activities against fluconazole-resistant isolates with MIC80 values ranging from 8 μg/mL to 16 μg/mL. Furthermore, compounds a6, a12 and a23 exhibited low inhibition profiles for CYP3A4. Clear SARs were analyzed, and the molecular docking experiment was carried out to further investigate the relationship between a6 and the target enzyme CYP51.

Comprehensive quantum mechanical studies on three bioactive anastrozole based triazole analogues and their SERS active graphene complex

Three triazole derivatives, 2-[3-(2-cyanopropan-2-yl)-5-(1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropanenitrile (anastrozole) (TR1), 3-amino-1-benzyl-5-phenyl-1H-1,2,4-triazole (TR2) and 5-amino-1-benzyl-3-phenyl-1H-1,2,4-triazole (TR3) were analyzed for the structural, nonlinear optical, electronic and biological properties. The functional nature of the compounds were analyzed using vibrational spectra and was compared with the scaled, simulated spectra obtained using DFT with diffused orbitals. Relaxed potential energy scan predicts the stable conformers. Frontier molecular orbital was found and used to generate some important data pertaining to the reactivity and stability of the molecule. Time dependent DFT was used to model the excitation and de-excitation dynamics of these molecules and to predict the use of these molecules as effective photo sensitizer in DSSC. This work further discusses in detail, NBO study for intra molecular interactions, MEP for reactivity preferences and hyperpolarizability calculations for predicting the optical properties. Further molecular docking studies were conducted for the compounds with CYP2C9 inhibitor (PDBID: 4NZ2), cytochrome P450 inhibitor (4D75), tyrosine-protein kinase JAK2 (4YTC), estragen synthase (4GL5) to predict their utility as potential. The compounds were found to interact with graphene monolayer results shows that there is enhancement in various physico-chemical descriptors and surface enhanced Raman spectra (SERS).

P2Y14 Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model

Eight P2Y14R antagonists, including three newly synthesized analogues, containing a naphthalene or phenyl-triazolyl scaffold were compared in a mouse model of chronic neuropathic pain (sciatic constriction). P2Y14R antagonists rapidly (≤30 min) reversed mechano-allodynia, with maximal effects typically within 1 h after injection. Two analogues (4-[4-(4-piperidinyl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxylic acid 1 and N-acetyl analogue 4, 10 μmol/kg, i.p.) achieved complete pain reversal (100%) at 1 to 2 h, with relief evident up to 5 h for 4 (41%). A reversed triazole analogue 7 reached 87% maximal protection. Receptor affinity was determined using a fluorescent antagonist binding assay, indicating similar mouse and human P2Y14R affinity. The mP2Y14R affinity was only partially predictive of in vivo efficacy, suggesting the influence of pharmacokinetic factors. Thus P2Y14R is a potential therapeutic target for treating chronic pain.

Annelation of substituted 3-Hydrazinylimidazo [2,1-c] [1,2,4]triazolone to a series of fused [1,2,4]triazepine and [1,2,4]triazine analogues and evaluation of their anticancer activity

Versatile straightforward synthetic pathways for a novel series of annelated imidazo [2,1-c] [1,2,4]triazole derivatives were performed. Our newly synthesized compounds were prepared from the reactive binucleophile 3-hydrazinyl-5-(4-methoxybenzylidene)-7-phenyl-5H-imidazo [2,1-c] [1,2,4] triazol-6(7H)-one 2 applying different synthetic strategies. The annelated derivatives are different imidazo [2′,1’:3,4] [1,2,4]triazolo [5,1-c] [1,2,4] triazepines 3–7; imidazo[2′,1’:3,4] [1,2,4]triazolo [5,1-c] [1,2,4,6]tetrazepine 8; imidazo[2′,1’:3,4] [1,2,4]triazolo [5,1-c] [1,2,4]triazines 9–15 and imidazo [1,2-d] [1,2,4]triazolo [4,3-b] [1,2,4]triazole analogue 16. Thirteen compounds have been subjected to screening for in vitro anticancer activity. This screening had been conducted at the National Cancer Institute (NCI), USA at a single dose (10-5 M) against full NCI 60 cell panel. The screening results indicated a considerable anticancer activity for compounds 7 and 13 against CNS cancer (SNP-75) cell line with growth inhibition percent 46.56 and 42.27, respectively. Moreover, a moderate anticancer activity against renal Cancer (UO-31) cell line was common with compounds 2, 7, 9, 11, 12, 13 and 15 with growth inhibition percent 31.54–39.52.

Synthesis of 2,1-Benzoisoxazole-Containing 1,2,3-Triazoles through Copper-Catalyzed Three-Component Domino Reactions of o-Bromoacetophenones, Aldehydes, and Sodium Azide

We herein describe an efficient copper-catalyzed three-component domino protocol used to prepare 2,1-benzoisoxazole-containing 1,2,3-triazoles from commercially available o-bromoacetophenones, aldehydes, and sodium azide. This domino process involves Aldol condensation, copper-catalyzed azide-chalcone oxidative cyclization, 1,2,3-triazole-assisted azidation, and denitrogenative cyclization sequences. The formed compounds could be considered as benzo[c]isoxazole-functionalized combretastatin A-4 triazole analogues, which might be potential applications in the discovery of a new anticarcinogen.

Molecular Docking Analysis of Triazole Analogues as Inhibitors of Human Neutrophil Elastase (HNE), Matrix Metalloproteinase (MMP 2 and MMP 9) and Tyrosinase

Triazole analogues are well known to have desirable properties for medicinal chemistry such as hydrogen bonding capability, moderate dipole character, rigidity and stability under in vivo conditions etc. This prompts us to carry out the present study, we have selected 20 triazole analogues and evaluated on the docking behavior of four targeted enzymes such as HNE, MMP 2, MMP 9 and tyrosinase. The molecular physicochemical analysis revealed that all the tested ligands (expect ligand 5 and 18) showed nil violation and complied well with the Lipinski's rule of five. ADME analysis showed that ligand 15 alone predicated to have low gastrointestinal (GI) absorption effect. Docking studies revealed that ligand 18 [2-(2,4-difluorophenyl)-1-(4-((1-(4-ethylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol] had exhibited the maximum binding energy for three target enzymes such as HNE, MMP 2 and MMP 9. The present study has paved a new insight in understanding 20 triazole analogues as potential inhibitors against HNE, MMP 2, MMP 9 and tyrosinase.

In-silico studies of novel triazole derivatives as inhibitor of 14a demethylase CYP51

An antifungal agent is a drug that eliminates fungal pathogens selectively from host with negligible toxicity to the host. Antifungal agents are classified into classes like antibiotics, antimetabolite, azole, and allyl amine. In this present work, the binding mode of novel designed triazole analogues with CYP51 has been investigated by flexible molecular docking. The molecular modeling, which gives the utilization of structural information of CYP51 can enhance the discovery of novel antifungal agents. Further in silico studies were performed in order to see their drug likeness properties and possible mode of interaction with target protein residue. Molecular docking of novel molecules was done by Schrodinger software using following steps like protein preparation, ligand preparation, grid generation, molecular docking. The protein PDB selected was 5V5Z. AZ3 analogue showed the best dock score. The docking value varied from -2.578 to-8.19 for the designed ligands. All the molecules showed good ADME properties and followed Lipinski rule of five. The designed molecules can serve as a lead for future antifungal drug discovery

Two groups of copperII pyridine-triazole complexes with "open or close" pepper rings and their in vitro antitumor activities.

Based on 1,2-dimethoxyphenyl (veratrole, open) and 1,2-methylenedioxyphenyl (pepper ring, close)-derived pyridine–triazole analogues, two groups of copper(ii) complexes, namely, Group I(C1–C3) and Group II(C4–C6) were synthesized and fully characterized. All ligands and complexes were tested in vitro by MTT assays on seven tumour cell lines (T24, Hep-G2, Sk-Ov-3, MGC-803, HeLa, A549 and NCI-H460) and one normal liver cell line (HL-7702). Surprisingly, the pepper-ring-derived complexes (C4–C6) showed significantly enhanced cytotoxicity compared with the 1,2-bimethoxyphenyl ring-derived complexes (C1–C3) and the standard anticancer drug cisplatin. Cellular uptake assays indicated that the Cu accumulation was consistent with cytotoxicity. In addition, flow cytometry and western blot analysis showed that the apoptosis of the leading complex C4 may be induced by the Bcl-2 family-mediated proteins through the mitochondrial dysfunction pathway. Furthermore, UV-vis and fluorescence spectroscopy assays revealed that C4 has stronger insertion-binding interactions with CT-DNA than C1 and the fluorescence of C1 and C4 with BSA is mainly quenched by static quenching.